Prostate cancer is a condition characterized by the uncontrolled proliferation of abnormal cells inside the prostate gland, part of the male reproductive system. Prostate cancer is the most common cancer among men and the second largest cause of cancer-related mortality in the United States. A novel approach to treating advanced Prostate cancer has emerged, attributable to the enhanced effectiveness of new pharmacological agents sourced from natural origins and this has led to increased rates of global existence and progression-free survival. Sesquiterpene lactones and their derivatives are now used worldwide to create and manufacture innovative cancer therapeutics. A thorough search was performed according to PRISMA guidelines in SciMed, PubMed, and Google Scholar, focusing on publications published from 1999 to 2024. The safety, efficacy, and bioactivity of sesquiterpene lactones must be evaluated via clinical trials, in vitro studies, and in vivo research and data was rigorously gathered and validated to verify its accuracy and usefulness. Prostate cancer may be treated far more effectively using naturally occurring sesquiterpene lactone molecules. The most prominent sesquiterpene lactones identified were artemisinin, alantolactone, costunolide, helenalin, cynaropicrin, parthenolide, and inuviscolide, which are originated from botanical sources like Ferula penninervis, Tanacetum argenteum, Artemisia kopetdaghensis, Cichorium intybus, Carpesium divaricatum, and Leptocarpha rivularis. Numerous studies indicated that sesquiterpene lactones may treat cancer by modifying many cellular signaling pathways, including PI3K/AKT, MAPK, JNK, NF-κB, TNF-α, and STAT3. Sesquiterpene lactones were shown to be significant in suppressing the proliferation of prostate cancer cell lines (DU-145, PC-3, LNCaP, MR49F, and BPH-1) in both laboratory and clinical settings.